Biomedical subjects

C Wolfman

Publications and source records attributed to C Wolfman.

13 recordsLinked to original sources

PubMed1992

Benzodiazepines in the brain. Their origin and possible biological roles.

Great progress has been made in the last 5 yr in demonstrating the presence of benzodiazepines (BDZs) in mammalian tissues, in beginning studies on the origin of these natural compounds, and in elucidating their possible biological roles. Many unanswered questions remain regarding the sources and biosynthetic pathways responsible for the presence of BDZs in brain and their different physiological and/or biochemical actions. This essay will focus on recent findings supporting that: (1) BDZs are of natural origin; (2) mammalian brain contains BDZs in concentrations ranging between 5 x 10(-10)-10(-8) M; (3) dietary source of BDZs might be a plausible explanation for their occurrence in animal tissues, including man; (4) the formation of BDZ-like molecules in brain is a possibility, experimentally supported; (5) BDZ-like molecules including diazepam and N-desmethyldiazepam are elevated in hepatic encephalopathy; and (6) natural BDZs in the brain are involved in the modulation of memory processes. Future studies using the full range of biochemical, physiological, behavioral, and molecular biological techniques available to the neuroscientist will hopefully continue to yield exciting and new information concerning the biological roles that BDZs might play in the normal and pathological functioning of the brain.

Animals↗

PubMed1992

Effect of various training procedures on performance in an elevated plus-maze: possible relation with brain regional levels of benzodiazepine-like molecules.

Rats submitted to one, two, or seven sessions of exploration to a new environment (habituation) or exposed to an inhibitory avoidance training showed different degrees of anxiety, evaluated by the elevated plus-maze test. Also, the brain regional levels of benzodiazepine (BDZ)-like molecules in rats submitted to one, two, or seven sessions of habituation were differentially decreased with respect to nontrained rats. The percentage of time spent in the open arms of the elevated plus-maze for each group correlates with the data of decrease in the BDZ-like immunoreactivity in amygdala (r = 0.77, p < 0.0005), hippocampus (r = 0.68, p < 0.0005), and septum (r = 0.57, p < 0.005). These results suggest that the limbic system responds to anxiogenic experiences by changing the BDZ-like molecule levels in relation to the degree of anxiety and/or stress that accompany these experiences.

Animals↗

PubMed1991

Habituation and inhibitory avoidance training alter brain regional levels of benzodiazepine-like molecules and are affected by intracerebral flumazenil microinjection.

The effects of habituation and inhibitory avoidance training on the rat brain regional levels of benzodiazepine (BZD)-like molecules and on central type BZD binding sites were examined. BZD-like immunoreactivity was decreased by 26-50% in the amygdala, cerebral cortex and septum of rats sacrificed immediately after stepping-down from the platform of an inhibitory avoidance apparatus (non-trained group) as compared to naive controls. Rats submitted to a second step-down session 20 h later (habituated group) have significantly lower BZD-like immunoreactivity in the septum (-60%) as compared to non-trained animals. Rats exposed to an inhibitory avoidance training, i.e. stepping-down and receiving a footshock (trained group), showed a significant reduction in the content of BZD-like molecules in cerebral cortex (-44%), amygdala (-68%), septum (-80%) and hippocampus (-82%) as compared to non-trained rats. In addition, the density of central type BZD binding sites was slightly increased in the hippocampus and septum of trained rats. No changes were observed in the apparent dissociation constant. No changes were observed in parallel measurements of [3H]-L-quinuclidinyl benzylate binding constants at cholinergic muscarinic binding sites. The immediate posttraining intrahippocampal bilateral injection of the central type BZD receptor antagonist flumazenil (10 nmol/hippocampus), enhanced the retention of habituation but not when injected in the amygdala or septum. In contrast, retention of the inhibitory avoidance task was significantly increased by flumazenil administered bilaterally into any of the 3 brain structures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Benzodiazepine receptor ligand influences on learning: an endogenous modulatory mechanism mediated by benzodiazepines possibly of alimentary origin.

In rats, pre- but not post-training ip administration of either flumazenil, a central benzodiazepine (BZD) receptor antagonist, or of n-butyl-B-carboline-carboxylate (BCCB), an inverse agonist, enhanced retention of inhibitory avoidance learning. Flumazenil blocked the enhancing effect of BCCB, and the inhibitory effect of the BZD agonists clonazepam and diazepam also given pre-training. Post-training administration of these drugs had no effect. The peripheral BZD receptor agonist/chloride channel blocker Ro5-4864 had no effect on the inhibitory avoidance task when given ip prior to training, but it caused enhancement when given immediately post-training either ip or icv. This effect was blocked by PK11195, a competitive antagonist of Ro5-4864. These results suggest that there is an endogenous mechanism mediated by BZD agonists, which is sensitive to inverse agonists and that normally down-regulates the formation of memories through a mechanism involving GABA-A receptors and the corresponding chloride channels. The most likely agonists for the endogenous mechanism suggested are the diazepam-like BZDs found in brain whose origin is possibly alimentary. Levels of these BZDs in the cortex were found to sharply decrease after inhibitory avoidance training or mere exposure to the training apparatus.

Animals↗

PubMed1991

Effect of post-training injections of flumazenil into the amygdala, hippocampus and septum on retention of habituation and of inhibitory avoidance in rats.

Adult rats were submitted to two different behavioral tasks using the same apparatus: the habituation of exploration of the apparatus considered as a novel environment as measured by the decrease in number of rearings and of ambulation between training and testing, and step-down inhibitory avoidance as measured by the increase in the latency to step down from a start platform onto an electrified grid between the training and the test session. The training-test interval for both tasks was 20 h. The immediate post-training injection of the benzodiazepine receptor antagonist flumazenil (10 nmol) bilaterally into the hippocampus enhanced retention of the two tasks. Application of the same drug, at the same dose to the septum or amygdala had no effect on habituation but enhanced retention of the avoidance task. The data are consistent with previous findings showing that both tasks are accompanied by the release of benzodiazepine-like immunoreactivity in the three structures and that this release is greater after the avoidance task. The present findings suggest a differential regional involvement of endogenous benzodiazepine-mediated mechanisms in memory modulation, according to the task undertaken.

Amygdala↗

PubMed1991

Memory modulation by brain benzodiazepines.

1. Recent evidence indicates that post-training memory processes are down-regulated by benzodiazepine/GABA-A systems in the amygdala, septum and hippocampus. Habituation and avoidance learning are accompanied by a decrease of benzodiazepine-like immunoreactivity in the three structures, explainable by a release of benzodiazepines. Immediate post-training microinjection of the benzodiazepine antagonist flumazenil into the hippocampus enhances retention of habituation. The post-training administration of flumazenil into any of the three structures enhances retention of avoidance learning. 2. The mode of operation of these systems was studied in detail in the amygdala using avoidance paradigms. The release of endogenous benzodiazepines during and particularly after training enhances sensitivity of local GABA-A receptors to muscimol, activation of the GABA-A receptors opens chloride channels that can be selectively blocked by picrotoxin and by Ro5-4864. Training enhances, and flumazenil reduces, sensitivity of the amygdala to the amnestic effect of locally injected muscimol by a factor of 100. Post-training intra-amygdala administration of picrotoxin or Ro5-4864 enhances retention. 3. These findings suggest that the endogenous benzodiazepine/GABA-A mechanisms that down-regulate memory in the amygdala, septum and hippocampus are activated in response to the anxiety and/or stress associated with each task. Memory lability which occurs in the post-training period and characterizes consolidation would thus be a consequence of the brain's response to anxiety or stress.

Animals↗

PubMed1990

Chrysin (5,7-di-OH-flavone), a naturally-occurring ligand for benzodiazepine receptors, with anticonvulsant properties.

Chrysin (5,7-di-OH-flavone) was identified in Passiflora coerulea L., a plant used as a sedative in folkloric medicine. Chrysin was found to be a ligand for the benzodiazepine receptors, both central (Ki = 3 microM, competitive mechanism) and peripheral (Ki = 13 microM, mixed-type mechanism). Administered to mice by the intracerebroventricular route, chrysin was able to prevent the expression of tonic-clonic seizures induced by pentylenetertrazol. Ro 15-1788, a central benzodiazepine receptor antagonist, abolished this effect. In addition, all of the treated mice lose the normal righting reflex which suggests a myorelaxant action of the flavonoid. The presence in P. coerulea of benzodiazepine-like compounds was also confirmed.

Animals↗

PubMed1990

Post-training down-regulation of memory consolidation by a GABA-A mechanism in the amygdala modulated by endogenous benzodiazepines.

In rats, amygdala benzodiazepine-like immunoreactivity decreases by 29% immediately after the animals step down from the platform of an inhibitory avoidance apparatus and decreases by a further 45% immediately after they receive a training footshock. The decrease is attributable to a release of diazepam or diazepam-like molecules. The immediate post-training intraamygdala injection of the central benzodiazepine antagonist flumazenil (10 nmole/amygdala) causes memory facilitation, and that of the GABA-A agonist muscimol (0.005 to 0.5 nmole) causes retrograde amnesia. Pretraining ip flumazenil administration (2.0 and 5.0 mg/kg) attenuates the effect of post-training muscimol by a factor of at least 100. The higher dose of pretraining flumazenil also causes memory facilitation. The data suggest that post-training consolidation is down-regulated by a GABA-A mechanism in the amygdala modulated by endogenous benzodiazepines released during training and at the time of consolidation.

Amygdala↗

PubMed1989

Benzodiazepine-like molecules, as well as other ligands for the brain benzodiazepine receptors, are relatively common constituents of plants.

The presence of benzodiazepine (BZD)-like molecules as well as of other substances with affinity for the brain BZD-receptors was explored in eight non-flowering plants known to contain biflavonoids, three flowering plants used as sedatives in folkloric medicine and one plant extensively used in Argentina, Uruguay, Brazil and Paraguay as a tea substitute. All the plants examined contained substances which bound to the central BZD-receptors and the majority of them also had BZD-like compounds detected by their specific interaction with a monoclonal antibody against BZDs. In various cases this last type of compound was present in amounts which exceeded trace levels (0.5-1.0 ng/g). The biological or clinical significance for humans of all these substances should be explored.

Antibodies, Monoclonal↗

PubMed1988

Proconvulsant and 'anxiogenic' effects of n-butyl beta carboline-3-carboxylate, an endogenous benzodiazepine binding inhibitor from brain.

The discovery of n-butyl beta carboline-3-carboxylate (beta CCB) as an endogenous substance of brain capable of interacting with the central benzodiazepine receptor, and the fact that this beta carboline increases in the cerebral cortex of rats undergoing acute stress, led us to study the pharmacological properties of beta CCB in mice. Using 3-mercaptopropionic acid in subconvulsant doses, it was found that this beta carboline, although not being a convulsant, has a proconvulsant action, as indicated by the number of mice undergoing convulsions and the reduction in latency. This proconvulsant effect was observed both with IP or ICV injections and was blocked by the benzodiazepine receptor antagonist RO 15-1788. In an open-field test the injection of 0.3 mg/kg of diazepam increased the number of squares crossed, while beta CCB had the opposite effect, reducing the squares crossed in a dose dependent manner between 1 and 30 mg/kg. This drug also increased the time of freezing and decreased the number of rearings. These changes were partially counteracted by the injection of 3.6 mg/kg of RO 15-1788. In the plus-maze test, 10 mg/kg chlordiazepoxide increased the number of entries and the time spent in the open arms, while the beta carboline produced the opposite effect. The conclusion reached is that beta CCB has both proconvulsant and anxiogenic actions, behaving as an inverse agonist for the central benzodiazepine receptor.

Animals↗

PubMed1984

Thyroid hormone regulation of adrenergic receptors and beta-adrenergic responsiveness in the rat submandibular gland.

The effects of altered thyroid function on the sensitivity of isoproterenol induced secretion of saliva and in the characteristics of adrenergic receptors from the rat submandibular gland were examined. Hyperthyroidism produced an increased sensitivity to beta-adrenergic stimulation of the gland, and this phenomenon was associated with an increase in the number of beta and alpha 1-adrenoceptors. On the other hand, surgical thyroidectomy produced a decrease sensitivity to isoproterenol stimulation of the submandibular gland and a diminished density of beta-adrenoceptors. In this case, no changes in alpha-adrenoceptors were observed. These results are discussed emphasizing the correlation between the functional control of saliva secretion and the adrenergic receptors in different thyroid states.

Animals↗

PubMed1983

Time course of changes in [3H]prazosin binding after catecholaminergic denervation by 6-hydroxydopamine in rat cerebral cortex. Inhibitory effects of ascorbic acid on the alpha 1-adrenoceptor.

The binding of [3H]prazosin to alpha 1-adrenoceptors was studied in membranes isolated from the rat cerebral cortex, at different times after the intraventricular injection of 6-hydroxydopamine. In controls, the binding was saturable with the Bmax = 113 pmol/g protein and KD = 0.93 nM, and revealed a single class of sites. After the action of the neurotoxin there was an increase in binding that reached +68% after 7 days and +35% after 14 days. This effect corresponded to an increase in Bmax (190 pmol/g protein) and a decrease in affinity (Kd = 2.1 nM), at 7 days after 6-hydroxydopamine. Carrying on experiments without ascorbic acid in the diluent, the well known inhibitory effect in vitro, that this drug has on the binding of several receptor ligands, was confirmed in vivo. The results obtained suggest that the noradrenergic denervation produced by the neurotoxin is capable of inducing adaptive changes, in alpha 1-post-synaptic adrenoceptors as measured by the binding of [3H]prazosin.

Animals↗

PubMedDate not supplied

Anxiogenic effects of the intraamygdala injection of flumazenil, a benzodiazepine receptor antagonist.

The effects of bilateral intraamygdala microinjection of flumazenil, a benzodiazepine receptor (BZD-R) antagonist, on the exploratory activity in an elevated plus maze were examined in chronically implanted rats. This compound induced a significant decrease in the time spent in the open arms, which is consistent with an anxiogenic action. No effect was observed after intrastriatal injections of flumazenil. Naive rats exposed to the elevated plus maze showed a rapid and selective decline in the content of BZD-like molecules in amygdala (-68%) but not in striatum and hippocampus. These data suggest that the anxiogenic effects of the intraamygdala injection of flumazenil is probably due to the blockade of BZD-like molecules released during the performance.

Amygdala↗